To investigate the mechanism of action of selected chemotherapeutic agents, and develop means to promote their potency and specificity. Approaches to these goals will be attempted by a combination of three routes: (1) Synthesis of analogs of known agents will be performed, in order to introduce modifications which should make them either more effective or of lesser general toxicity. (2) Alteration of the nutritional status of tumor cells will be carried out, both in culture or in vivo, to produce conditions interfering with the metabolic inactivation of the chemotherapeutic agent. This approach will be particularly directed against resistant cell varieties and will be carried out by introduction of deficiencies accompanied with available or newly synthesized antimetabolites. (3) Modification of the cell membrane of susceptible and resistant varieties of tumor cells will be attempted with the use of either available or newly synthesized membrane-reactive agents. Studies will be performed to estimate their effects on permeability and susceptibility to chemotherapeutic agents.